Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
  • C07J53/002—Carbocyclic rings fused
  • C07J53/004—3 membered carbocyclic rings
  • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

• the present invention relates to a process for the epoxidation of 17-oxo-15,16-methylene steroids, in particular of drospirenone precursors.
• Drospirenone (I) is a synthetic steroid with progestin, antimineralocorticoid and antiandrogen activity, used as contraceptive.
• the synthesis of this compound comprises the conversion of a steroid precursor containing a C 17 keto group to the corresponding spironolactone. This conversion is usually carried out with carbanions, such as propargyl alcohol derivatives, as disclosed in US 6,121,465 , US 2005/0192450 and EP 0075189 .
• US 4,129,564 discloses the preparation of 17-spironolacto-steroids comprising the use of lithium and 1-bromo-3-dimethoxy-propane. J. Med. Chem. 1987, Vol. 30, n.
• the present invention relates to a process for the epoxidation of 17-oxo-15,16-methylene-steroids, in particular of drospirenone precursors (I) which comprises the treatment of a 17-oxo-15,16-methylene steroid with a sulfoxonium ylide, in particular with dimethysulfoxonium methyl ylide, commonly known as Corey-Chaykovsky reagent.
• This reagent can be prepared by treatment of trimethylsulfoxonium salts, for example trimethylsulfoxonium chloride or iodide, with a strong base.
• a preparation procedure is for example disclosed in L.F. Fieser & M. Fieser, Reagents for Organic Synthesis, J. Wiley & Sons, Inc., N.Y., 1967, p. 315 .
• the resulting spiroepoxides can be subjected to a reaction sequence leading to the desired steroid derivative.
• the spiroepoxide is reacted with diethyl malonate to give the corresponding 3-carboxy-spironolactone which, after decarboxylation, provides spironolactone, as illustrated in Scheme 1.
• the epoxidation reaction is usually carried out with 1 to 10 equivalents of reagent, preferably from 2 to 5 equivalents, in an anhydrous aprotic organic solvent, preferably selected from dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, sulfolane or ethers and mixtures thereof, such as tetrahydrofuran, dioxane and dimethoxyethane, at a temperature ranging from -10 to 50°C.
• anhydrous aprotic organic solvent preferably selected from dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, sulfolane or ethers and mixtures thereof, such as tetrahydrofuran, dioxane and dimethoxyethane, at a temperature ranging from -10 to 50°C.
• the epoxidation reaction is carried out on a steroid substrate which can be subsequently converted to drospirenone according to known methods or as hereinafter disclosed.
• the process comprises the reaction sequence illustrated in Scheme 2:
• the process comprises the reaction sequence illustrated in Scheme 3:
• the process comprises the reaction sequence illustrated in Scheme 4.
• the intermediate 15,16-methylene-17-spiro epoxides are novel and are also object of the present invention.
• the following compounds are preferred:
• This mixture was cooled to 0°C and added with a solution of 73.5 g sodium hydroxide in 1100 ml water, then stirred at room temperature for 20 hours.
• the suspension was cooled to 0°C and added with 184 ml 35% hydrochloric acid to adjust the pH from 1 to 2; stirring at 0°C was continued for 3 hours and the suspension was filtered and the resulting solid was washed with water.
• a suspension of 30 g 3 ⁇ -hydroxy-15 ⁇ ,16 ⁇ -methyleneandrost-5-en-17-one in 500 ml toluene was added with 50 ml cyclohexanone and 7.56 g aluminium isopropoxide, stirring under reflux for 1 hour.
• the mixture was cooled to room temperature and added with 500 ml methylene chloride and 300 ml 1 M sulfuric acid; the phases were separated and the organic one was washed with 300 ml water, then concentrated under vacuum.
• a mixture of 15 g 15 ⁇ ,16 ⁇ -methyleneandrost-4-en-3,17-dione, 300 ml ter-butanol and 18.5 g tetrachloro-p-benzoquinone was refluxed for 3 hours. After cooling at 30°/40°C, the insolubles were filtered off and the mother liquor was concentrated under vacuum. The residue was taken up with 300 ml methylene chloride and 150 ml water; the suspension was filtered and the liquid phases were separated; the organic one was washed with 2 x 150 ml water; the phases were separated and the organic one was added with a 5% sodium hydroxide solution (450 ml); the suspension was filtered through Celite and the liquid phases were separated.
• the organic phase was washed with a 5% sodium hydroxide solution (2 x 150 ml); the phases were separated and the organic one was washed with a 4% sodium chloride solution (3 x 150 ml).
• the organic phase was concentrated under vacuum and the residue was taken up with 50 ml tert-butyl methyl ether, cooled to 0°/5°C for 30 minutes and the resulting suspension was filtered.
• the mixture was cooled at 0°C and added with a solution of 2.4 g sodium hydroxide in 40 ml water, stirring at room temperature for 20 hours.
• the solution was cooled at 0°C and the pH was adjusted to 1 - 2 with 35% hydrochloric acid, stirring at 0°C for 3 hours; the resulting suspension was filtered and washed with water.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)

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Cited By (13)

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• 2006
  • 2006-09-22 IT IT001802A patent/ITMI20061802A1/it unknown
• 2007
  • 2007-09-19 EP EP07018400A patent/EP1903051A3/fr not_active Withdrawn
  • 2007-09-21 US US11/858,976 patent/US20080076915A1/en not_active Abandoned

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